1. Field of the Invention
This invention relates generally to analogs of human chemokines and methods of using them in the prevention, treatment, and ameliorization of diseases that can benefit from therapeutic angiogenesis.
2. Description of the State-of-the-Art
Therapeutic angiogenesis is a relatively new procedure that is recognized as a viable treatment strategy for increasing the supply of blood to a tissue in the treatment of a disease. Angiogenesis is generally described as the growth of new blood vessels, and there are many medical situations in which an increase in blood supply is indicated. In a broad sense, this growth of new blood vessels can be derived from an old blood vessel or from bone marrow-derived cells, such as endothelial progenitor cells and hematopoietic stem cells.
Examples of such situations include, for example, tissue injuries, such as burns and wound healing, where an increased blood supply can increase the rate of healing and reduce the risk of infection; cardiovascular diseases, where an increased blood supply can assist in the repair of cardiac tissue; peripheral vascular diseases, where an increased blood supply can assist in providing sufficient oxygen and nutrients to extremities; a stroke, where an increased blood supply can reduce the risk of transient ischemic attacks and vascular deficiencies that can create damage to brain tissue; diabetes, which often includes peripheral vascular disease, for example; and cancer, where drug treatments can be improved by inducing angiogenesis in a tumor to facilitate transport of a drug into the cancerous tissue. Accordingly, the methods taught herein have many uses, of which a predominant use includes the treatment of ischemic conditions associated with various diseases.
Ischemia is a condition involving a restricted blood flow to a tissue and is the most common consequence of vessel dysfunction. Ischemic conditions result in a disruption of oxygen and nutrient delivery to tissue, as well as the accumulation of waste metabolites in tissue. Cells cannot survive an extended case of severe ischemia but may be able to adapt to a moderate condition where diffusion to and from a bordering non-ischemic region is capable of sustaining vital cellular functions. Under these moderate conditions, the secondary functions of affected tissues may be impaired, and a new metabolic equilibrium may be established depending on the level of cross-diffusion and hypoxia present in the tissue.
In fact, in tissues that normally have a high metabolic turnover, such as skeletal and cardiac muscle, even a mild case of ischemia can create serious conditions that include hypoxia, acidosis, and a depressed tissue function that may eventually threaten the viability and function of the tissue. Ischemic cardiac muscle, for example, is particularly vulnerable to a “reperfusion injury” from ischemia, because the reperfusion that usually must occur in an ischemic cardiac muscle to restore its function introduces free radicals to the ischemic tissue during the reoxygenation process. In fact, the reperfusion injury can sometimes cause as much damage as the ischemic condition itself.
The options available to one of skill in the art of preventing and treating ischemia are currently limited. The administration of lipid/cholesterol-lowering agents, diet, and anti-platelet adherence therapy (e.g. treatment with aspirin) may help slow the progression of vessel disease in some instances; but surgery may still be the only option in advanced stages of the disease. Such surgeries can include coronary artery bypass grafting and percutaneous transluminal coronary angioplasty. Unfortunately, even surgery may not be an option at times. In some cases, the only treatment option may be limited to activating endogenous angiogenic or arteriogenic pathways to stimulate revascularization of the ischemic tissue.
Diseases that include the complications of ischemia remain a large problem faced by our society. Cardiovascular disease is responsible for over 17 million deaths worldwide each year, and coronary heart disease is the biggest contributor. Coronary artery disease is a contributor that, alone, is responsible for over 550,000 deaths each year in the United States. Peripheral vascular diseases create ischemic conditions that result in limb amputations for over 150,000 patients each year, and these patients have a subsequent mortality rate of about 40% within two years of amputation.
Our society can benefit significantly from the introduction of therapeutic methods that can reduce or eliminate the need for surgical procedures. The present invention is based on the discovery that select analogs of the chemokines known as stromal cell-derived factor-1 (SDF-1) and interleukin-8 (IL-8) are effective at inducing endothelial cell differentiation, neo-vessel formation and, furthermore, angiogenesis in tissue. Accordingly, those skilled in the art will appreciate the novel and effective methods that are taught herein. The teachings represent a valuable contribution to the field of therapeutic angiogenesis, a relatively new field that has been developed to prevent, treat, and ameliorate symptoms of, diseases affecting the circulatory system.